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Background The latest clinical guidelines are mandatory for physicians to follow when practicing evidence-based medicine in the treatment of low back pain. Those guidelines should target not only Japanese board-certified orthopaedic surgeons, but also primary physicians, and they should be prepared based entirely on evidence-based medicine. The Japanese Orthopaedic Association Low Back Pain guideline committee decided to update the guideline and launched the formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline with the latest data of evidence-based medicine. Methods The Japanese Orthopaedic Association Low Back Pain guideline formulation committee revised the previous guideline based on a method for preparing clinical guidelines in Japan proposed by Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Two key phrases, "body of evidence" and "benefit and harm balance" were focused on in the revised version. Background and clinical questions were determined, followed by literature search related to each question. Appropriate articles were selected from all the searched literature. Structured abstracts were prepared, and then meta-analyses were performed. The strength of both the body of evidence and the recommendation was decided by the committee members. Results Nine background and nine clinical qvuestions were determined. For each clinical question, outcomes from the literature were collected and meta-analysis was performed. Answers and explanations were described for each clinical question, and the strength of the recommendation was decided. For background questions, the recommendations were described based on previous literature. Conclusions The 2019 clinical practice guideline for the management of low back pain was completed according to the latest evidence-based medicine. We strongly hope that this guideline serves as a benchmark for all physicians, as well as patients, in the management of low back pain.

Study Design: Retrospective case-control study Objectives: To determine whether diffuse idiopathic skeletal hyperostosis (DISH) can be diagnosed based on anterior longitudinal ligamental ossification in the lumbar spine using plain lumbar spine X-ray images. Methods: This study included 100 patients (59 men and 41 women; mean age, 64.8 ± 13.8 years; range, 27-89 years) who underwent computed tomography (CT) of the chest to the pelvis in our hospital and plain lumbar spine radiography within 6 months before and after CT scanning. DISH was diagnosed based on the thoracolumbar spine CT findings using Resnick’s diagnostic criteria. The patients were grouped according to DISH diagnosis into the DISH (+) and DISH (−) groups. On the frontal and lateral lumbar spine X-ray images, each spinal level from Th11/12 to L5/S was scored based on the Mata scoring system. The distribution of the Mata scores was compared between the 2 groups. Results: Forty (40%) patients were diagnosed with DISH based on the CT findings. A cutoff value ≥8 provided a sensitivity of 75% and specificity of 100% for diagnosing DISH, thus, indicating the validity of the cutoff value. In the DISH (−) group, no patient had ≥3 consecutive spinal levels with a Mata score ≥2, suggesting that DISH can be diagnosed on the basis of at least 3 consecutive spinal levels with a Mata score ≥2. Conclusion: On lumbar spine X-ray images of the T11/12 to L5/S levels, a Mata score ≥2 for at least 3 consecutive levels or a total score ≥8 strongly indicates the presence of DISH.

Several studies have reported the prognostic factors for soft tissue sarcoma. Although serum lactate dehydrogenase (LDH) levels are associated with poor prognosis in several types of cancer, their role in soft tissue sarcomas remains unclear. Therefore, the present study evaluated the association between serum LDH levels and the clinical characteristics and prognosis of soft tissue sarcoma. A total of 103 patients diagnosed with primary soft tissue sarcoma between 2003 and 2019 were retrospectively examined, and the association between serum LDH levels at the first visit and clinical characteristics were analysed. In high-grade soft tissue sarcoma, the association between survival and clinical characteristics, including stratified LDH levels, was also analysed. Serum LDH levels were stratified (253 and ≤253 IU/l) according to the standard values used at our institution. High serum LDH levels were significantly associated with the presence of metastasis and histological grade (P0.001 and 0.040, respectively). In both the univariate and multivariate analyses, disease-specific survival (DSS) was significantly worse in patients with high-grade soft tissue sarcoma and high serum LDH levels than in patients with normal serum LDH levels (univariate analysis: P=0.025; multivariate analysis: Hazard ratio, 4.60; 95% confidence interval, 1.16-18.2; P=0.030). In conclusion, high serum LDH levels at the first visit predicted the presence of distant metastasis, high histological grade and worse DSS in patients with high-grade soft tissue sarcoma. Therefore, in patients with high serum LDH levels at the first visit, these risks should be considered during pretreatment examinations and post-treatment follow-up.

Retrospective case-control study.To investigate the prevalence and characteristics of diffuse idiopathic skeletal hyperostosis (DISH) in vertebral fracture patients admitted to our hospital.Although vertebral fracture is generally treated conservatively with rest and use of a corset, surgery with rigid internal fixation is recommended for vertebral fractures in patients with DISH. Thus, treatment strategies for vertebral fracture differ according to the presence or absence of DISH. However, only a few studies have investigated the prevalence of DISH in vertebral fracture patients.A total of 159 patients (49 men and 110 women, with a mean age of 82.9 years) who were diagnosed with fresh vertebral fracture and required admission to HITO Hospital. The diagnosis of fresh vertebral fracture was made using x-ray imaging, computed tomography, and magnetic resonance imaging, and the presence or absence of DISH was assessed. In addition, age, sex, bone mineral density ( % young adult mean), blood test results, treatment, and length of hospital stay were compared between patients with and without DISH.The proportion of patients with DISH among the patients with vertebral fracture was 33.9% (54 of 159 patients). The proportions in men and women were 38.8% and 31.8%, respectively, with no significant difference between sexes (P = 0.39). The patients in the DISH group were older than those in the non-DISH group (83.6 vs. 79.4 years, P = 0.009), and the DISH group had higher glycated hemoglobin A1c (P = 0.005), higher bone mineral density (P = 0.042), and longer length of hospital stay (P = 0.0001) compared with those in the non-DISH group.The proportion of patients with DISH among the vertebral fracture patients was 33.9%. Given that patients with DISH may require different treatment approaches, careful observation is needed.3.

Study Design: Retrospective observational study. Objective: To investigate the relationship between the extent of ligament ossification and the range of motion (ROM) of the lumbar spine and develop a new scoring system. Methods: Forty-three patients (30 men and 13 women) with lumbar spinal canal stenosis who underwent decompression from January to December 2018. Ligament ossification at L1/2 to L5/S was assessed on plain X-ray (Xp) and computed tomography (CT) using a modified Mata scoring system (0 point: no ossification, 1 point: ossification of less than half of the intervertebral disc height, 2 points: ossification of half or more of the intervertebral disc height, 3 points: complete bridging), and the intra-rater and inter-rater reliability of the scoring was assessed. The relationship of the scores with postoperative lumbar ROM was investigated. Result: Intra-rater reliability was high (Cronbach’s α was 0.74 for L5/S on Xp but 0.8 or above for other sections), as was inter-rater reliability (Cronbach’s α was 0.8 or above for all the segments). ROM significantly decreased as the score increased (scores 1 to 2, and 2 to 3). A significant moderate negative correlation was found between the sum of the scores at L1/2-L5/S and the ROM at L1-S (ρ = − 0.4493, P = 0.025). Conclusion: Our scoring system reflects lumbar mobility and is reproducible. It is effective for assessing DISH in fractures and spinal conditions, and monitoring effects on treatment outcomes and changes over time.

A 74-year-old man developed bilateral lower limb spastic paresis. He was diagnosed with thoracic spondylotic myelopathy presumably caused by mechanical stress that was generated in the intervertebral space (T1-T2) between a vertebral bone bridge (C5-T1) due to diffuse idiopathic skeletal hyperostosis after anterior fixation of the lower cervical spine and a vertebral bone bridge (T2-T7) due to diffuse idiopathic skeletal hyperostosis in the upper thoracic spine. Treatment included posterior decompression (T1-T2 laminectomy) and percutaneous pedicle screw fixation at the C7-T4 level. Six months after surgery, the patient could walk with a cane, and the vertebral bodies T1-T2 were bridged without bone grafting. For thoracic spondylotic myelopathy associated with diffuse idiopathic skeletal hyperostosis, decompression and percutaneous pedicle screw fixation are effective therapies.

Many studies have evaluated surgical treatments for spinal deformities in patients with neuromuscular disease. However, few reports have described patients with Fukuyama congenital muscular dystrophy (FCMD). A 13-year-old boy with FCMD was unable to sit for long periods or sleep in the supine position because of progressive scoliosis. His Cobb angle worsened from 27° to 41° in 5months. He underwent standard posterior spinal fusion and pedicle-screw-alone fixation from T5 to S1. Postoperatively, his Cobb angle improved from 41° to 25° without exacerbation for 2years. After the surgery, he was able to sit for longer periods without pain, and he and his family were satisfied with the efficacy of the spinal fusion. Some patients with mild FCMD can sit at the age of puberty, but progression to scoliosis is possible. Therefore, spinal fusion for progressive scoliosis in patients with FCMD should be considered.

Background Thoracic spondylotic myelopathy (TSM) commonly occurs at the thoracolumbar junction, and mechanical stress is thought to be involved. In DISH, the anterior longitudinal ligament becomes ossified. Although DISH is suspected to be involved in TSM pathology, reports are limited. Aim of this study is to investigate the association between (TSM) and diffuse idiopathic skeletal hyperostosis (DISH). Methods Fifty-one patients with thoracic myelopathy underwent surgery between April 2008 and April 2017. Of these, 28 patients with TSM were included and examined. DISH was confirmed using computed tomography (CT). Subjects were divided into DISH and non-DISH sub-groups according to CT findings, and the DISH coexistence rate was calculated. Groups were analyzed for sex, age, postoperative Japanese Orthopedic Association (JOA) score, and reoperation status. In the DISH group, the positional relationship between the affected vertebral level of TSM and consecutive vertebral bone bridges was analyzed. Patients without spinal disease matched for sex and age were enrolled as controls (N = 56). The DISH coexistence rate was compared and analyzed between groups. Results Mean age at surgery was 67.8 years (43–82 years; 22 men, 6 women). DISH was detected in 17 of 28 patients (60.7%; 15 men, 2 women). No significant difference in the improvement rate of JOA score was observed between groups. TSM occurred at: lower border of a consecutive vertebral bone bridge, N = 4; upper border, N = 3; between consecutive vertebral bone bridges, N = 5; one vertebral body away from a consecutive vertebral bone bridge, N = 5. No patient had TSM occurring within a consecutive vertebral bone bridge. The DISH coexistence rate in patients with TSM (60.7%) was significantly higher than that in controls (20/56, 35.7%) (p = 0.03). Conclusion Mechanical stress caused by consecutive vertebral bone bridges due to DISH may be involved in TSM pathogenesis. Therefore, in DISH patients, attention needs to be paid to TSM onset.

Study design A retrospective cohort study. Purpose To investigate the risk factors for postoperative delirium after spine surgery, excluding older age, which has already been established as a strong risk factor. Overview of literature More than 30 risk factors have been reported for delirium after spine surgery, making it challenging to identify which factors should be prioritized. We hypothesized that risk factors could not be prioritized to date because the factor of older age is very strong and influenced other factors. To eliminate the influence of older age, we performed an age-matched group comparison analysis for the investigation of other risk factors. Methods This study involved 532 patients who underwent spine surgery. Two patients of the same age without delirium (delirium negative group) were matched to each patient with delirium (delirium positive group). Differences in suspected risk factors for postoperative delirium between the two groups identified from previous reports were analyzed using univariate analysis. Multivariate analysis was performed for factors that showed a significant difference between the two groups in the univariate analysis. Results Fifty-nine (11.1%) of 532 patients developed postoperative delirium after spine surgery. Large amounts of intraoperative bleeding, low preoperative concentration of serum Na, high postoperative (day after surgery) serum level of C-reactive protein, low hematocrit level, low concentration of albumin, and high body temperature were detected as significant risk factors in the univariate analysis. Large amounts of intraoperative bleeding remained a risk factor for postoperative delirium in the multivariate analysis. Conclusions We should pay attention to and take precautions against the occurrence of postoperative delirium after spine surgery in patients of older age or those who experience severe intraoperative bleeding.

Despite the availability of several modalities of treatment, including surgery, pharmacological agents, and nerve blocks, neuropathic pain is often unresponsive and sometimes progresses to intractable chronic pain. Although exercise therapy is a candidate for treatment of neuropathic pain, the mechanism underlying its efficacy has not been elucidated. To clarify the molecular mechanism for pain relief induced by exercise, we measured Rnf34 and Pacap mRNA levels in the spinal cord dorsal horn of SNL rats, a model of neuropathic pain. SNL model rats exhibited stable mechanical hyperalgesia for at least 6 weeks. When the rats were forced to exercise on a treadmill, mechanical and thermal hyperalgesia were significantly ameliorated compared with the non-exercise group. Accordingly, gene expression level of Rnf34 and Pacap were also significantly altered in the time course analysis after surgery. These results suggest that exercise therapy possibly involves pain relief in SNL rats by suppressing Rnf34 and Pacap expression in the spinal cord.

Background Adenosine is an endogenous neuromodulator in both the peripheral and central nervous systems. Adenosine inhibits pain signals by hyperpolarizing neuronal membrane. Methods To clarify the effects of adenosine on pain signals, we tested intrathecal adenosine injection in two neuropathic pains (spinal cord compression and chronic constriction of sciatic nerve) and postoperative pain (plantar incision). Results In all three kinds of pain models, significant shortening of withdrawal latencies to thermal stimulation were detected from 24 h to 1 week after the surgery. Significant improvements of pain sensation were observed in all three models after intrathecal injection of Cl-adenosine 24 h after surgery. At 72 h after surgery, intrathecal Cl-adenosine injection inhibited hyperalgesia in the two neuropathic pain models but not in the postoperative pain model. Adenosine A1R messenger RNA (mRNA) expression significantly decreased in the plantar incision model. Adenosine A1R protein levels also decreased compared with the other two models and normal control. Conclusions These results suggest that adenosine effectively inhibits pain signals in neuropathic pain but is less effective in postoperative pain because of the decrease in adenosine A1 receptors.

We developed a novel thermoelectric cooling device using Peltier modules for the treatment of spinal cord injury in rats. The extracorporeal electrically cooling component was attached to the aluminum arched plate which was placed on the surface of the spinal cord after the contusion injury in the 11th thoracic spinal cord. During the hypothermic treatment, rats were awake and could move in the cage. Hind limb motor function, evaluated using a BBB scale, in the hypothermic animals (33°C for 48 h) was significantly higher than that in the normothermic animals from 2 weeks to 8 weeks after the injury.

The effect of intracellular cyclic guanosine monophosphate (GMP) increase on neuronal damage was tested using a newly developed nitric oxide-related injury model of cultured spinal cord neurons.Neuronal damage after 24-hour-exposure to sodium nitroprusside (SNP), a nitric oxide (NO) donor, was evaluated by measuring the activity of released lactate dehydrogenase from injured neurons.Oxygen radical scavengers had a protective effect, indicating that the neuronal damage, elicited by 10 μM SNP, was largely due to peroxynitrite formation. Alternatively, a strong inhibition of the NO-induced damage could also be achieved by an intracellular cyclic GMP increase resulting from the addition of 100 μM 8-bromo-cyclic GMP. Propentofylline (PPF, 1-100 μM), a xanthine derivative and rather selective phosphodiesterase (PDE) inhibitor, enhanced intracellular cyclic GMP elevation induced by SNP exposure. The neuronal damage induced by 10 μM SNP exposure for 24 hours was almost completely blocked in the presence of 1 μM PPF.These results suggest that NO has an ambiguous action, i.e. toxic by favoring the formation of, but protective by intracellular cyclic GMP elevation which can be reinforced by PDE inhibition. Therefore, PDE inhibitors, such as PPF, may be useful therapeutic drugs to limit oxidative neuronal damage in the central nervous system.

An in vivo study using a spinal cord compression model in rats. To evaluate the effect of adenosine on thermal hyperalgesia after spinal cord injury (SCI). After SCI, some patients suffer dysesthesia that is unresponsive to conventional treatments. We previously established a rat thoracic spinal cord mild-compression model by which we were able to induce thermal hyperalgesia in the hind limbs. The thoracic spinal cord was compressed gently using a 20-g weight for 20 min. The withdrawal latency in response to thermal stimulation was monitored bilaterally in the hind limbs using Hargreaves’ Plantar test apparatus. SCI-induced thermal hyperalgesia was mimicked by the intrathecal application of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist. Hyperalgesia induced by SCI was significantly inhibited by the intrathecal application of 10–30 nmol chloro-adenosine (Cl-adenosine), a nonselective adenosine receptor agonist. The effect of Cl-adenosine (10 nmol) on hyperalgesia after SCI was blocked by the simultaneous application of DPCPX. Intrathecal application of R(−)N6-(2phenylisopropyl) adenosine (R-PIA; 10 nmol), a selective A1 receptor agonist, also inhibited SCI-induced hyperalgesia. In contrast, intrathecal application of CGS21680, a selective adenosine A2a receptor agonist, did not inhibit SCI-induced hyperalgesia. These results suggest that adenosine inhibits hyperalgesia through the stimulation of A1 receptors. Adenosine or adenosine A1 receptor agonists should be considered as candidates for new therapeutic methods for treating post-SCI dysesthesia.

An in vivo study using a spinal cord compression model in rats. To evaluate the effect of prostaglandin E1 (PGE1) on the change in thoracic spinal cord blood flow and on hind-limb motor function. Until now, effect of PGE1 on spinal cord blood flow at the point of compression has not been tested. Our newly developed blood flow measurement system was a combination of a noncontact-type Laser Doppler system and a spinal cord compression device. The rat thoracic spinal cord was exposed and spinal cord blood flow at the point of compression was measured before, during and after compression. The functioning of the animals' hind-limbs was evaluated by the BBB Scale and by measuring the frequency of voluntary standing. During the compression period, spinal cord blood flow was significantly higher in the PGE1-treated rats than in the control rats, which did not receive PGE1. After decompression, the spinal cord blood flow rapidly recovered to about 60% of the precompression level in the control rats. When the animals were treated with PGE1, blood flow after decompression reached about 90% of the precompression level. Twenty-gram compression for 40 mins induced motor deficiencies in the rat hind-limbs. The application of PGE1 significantly improved motor function of the rat hind-limbs after spinal cord injury. The application of PGE1 increased spinal cord blood flow during and after spinal cord compression, and improved motor function after the spinal cord injury.

To develop a novel genetic approach for the treatment of pain, we tested the transplantation of gene-transferred autologous macrophages by lumbar puncture. A rat neuropathic pain model was produced by chronic constriction of the sciatic nerve. Autologous macrophages were collected from the intraperitoneal space. Then human proenkephalin gene was transferred into the macrophages by electroporation. The gene-transferred macrophages were transplanted into the subarachnoid space by lumbar puncture. One week after transplantation, the heat hyperalgesia and allodynia induced by sciatic nerve constriction completely remitted. The analgesic action continued until at least 4 weeks after transplantation. The transplanted macrophages migrated into the spinal cord and expressed proenkephalin mRNA and Met-enkephalin protein. The method we tested in the present study may be a safe, simple and effective way to inhibit pain sensation after peripheral nerve injuries.

A basic study using a spinal cord injury (SCI) model in rats.The effect of mild hypothermic treatment on histological changes and motor function after a rat spinal cord compression injury was assessed.Mild spinal cord compression was performed at the eleventh thoracic vertebral level by a 20 g weight for 20 min. Rats in the mild hypothermic model were kept at a body temperature of 33 degrees C and rats in the normothermic group were kept at 37 degrees C for 1 h from beginning of compression. Motor function was evaluated by measuring the frequency of standing. Microglia were stained by isolectin B4 and observed in the compressed portion of the spinal cord. The amount of tumor necrosis factor-alpha (TNF-alpha) in the compressed spinal cord was measured by the ELISA method.In the normothermic rats, microglia proliferated up to 72 h after the compression. Proliferation was substantially inhibited at 48 and 72 h after compression in the hypothermic rats. The motor function of the hypothermic rats improved at 48 and 72 h after the compression, whereas no improvement was seen in the normothermic rats. The amount of TNF-alpha in the compressed portion of the spinal cord was lower in hypothermic rats compared with normothermic rats throughout the experiment.These results suggest that hypothermic treatment is effective for the amelioration of delayed motor dysfunction via inhibition of microglial inflammatory responses.

An in vivo study to measure rat spinal cord blood flow in real-time at the site of compression using a newly developed device.To evaluate the change in thoracic spinal cord blood flow by compression force and to clarify the association between blood flow recovery and motor deficiency after a spinal cord compression injury.Until now, no real-time measurement of spinal cord blood flow at the site of compression has been conducted. In addition, it has not been clearly determined whether blood flow recovery is related to motor function after a spinal cord injury.Our blood flow measurement system was a combination of a noncontact type laser Doppler system and a spinal cord compression device. The rat thoracic spinal cord was exposed at the 11th vertebra and spinal cord blood flow at the site of compression was continuously measured before, during, and after the compression. The functioning of the animal's hind-limbs was evaluated by the Basso, Beattie and Bresnahan scoring scale and the frequency of voluntary standing. Histologic changes such as permeability of blood-spinal cord barrier, microglia proliferation, and apoptotic cell death were examined in compressed spinal cord tissue.The spinal blood flow decreased on each increase in the compression force. After applying a 5-g weight, the blood flow decreased to40% of the precompression level. Complete ischemia was reached using a 20-g weight. After decompression, the blood flow level in the 20-minute complete ischemia group was significantly higher than that in the 40-minute complete ischemia group. The hind-limb motor function in the 40-minute complete ischemia group was significantly less than that in the sham group (without compression), while no significant difference was observed between the 20-minute ischemia group and the sham group. In the 20-minute ischemia group, the rats whose spinal cord blood flow recovery was incomplete showed significant motor function loss compared with rats that completely recovered blood flow. Extensive breakdown of blood-spinal cord barrier integrity and the following microglia proliferation and apoptotic cell death were detected in the 40-minute complete ischemia group.Duration of ischemia/compression and blood flow recovery of the spinal cord are important factors in the recovery of motor function after a spinal cord injury.

Elucidation of the process of degeneration of injured axons is important for the development of therapeutic modules for the treatment of spinal cord injuries. The aim of this study was to establish a method for time-lapse observation of injured axons in living animals after spinal cord contusion injury. YFP (yellow fluorescent protein)-H transgenic mice, which we used in this study, express fluorescence in their nerve fibers. Contusion damage to the spinal cord at the 11th vertebra was performed by IH (Infinite Horizon) impactor, which applied a pressure of 50 kdyn. The damaged spinal cords were re-exposed during the observation period under anesthesia, and then observed by two-photon excited fluorescence microscopy, which can observe deep regions of tissues including spinal cord axons. No significant morphological change of injured axons was observed immediately after injury. Three days after injury, the number of axons decreased, and residual axons were fragmented. Seven days after injury, only fragments were present in the damaged tissue. No hind-limb movement was observed during the observation period after injury. Despite the immediate paresis of hind-limbs following the contusion injury, the morphological degeneration of injured axons was delayed. This method may help clarification of pathophysiology of axon degeneration and development of therapeutic modules for the treatment of spinal cord injury.

P38 mitogen-activated protein kinase (MAPK) is one of the key enzymes in apoptosis induction pathways. We tested continuous intrathecal infusion of SB203580, a selective inhibitor of p38-MAPK, after spinal cord compression injury by a 20 g weight for 40 min at the 11th vertebra level-thoracic spinal cord. SB203580 (1 μg/day) was infused for 1 week after the compression. Hind-limb function was evaluated by measuring the frequency of ‘standing’ posture; raising fore limbs and sustaining body weight with hind-limbs. One-week after the compression, frequency of standing spinal cord injured rat was decreased to about half of that in sham operated animals which underwent laminectomy without compression. The frequency of standing in rats infused SB203580 recovered 2–3 weeks after the spinal cord injury, on the other hand, vehicle animals infused with saline did not recover. Myelin staining by Luxol fast blue showed severe myelin degradation in vehicle animals in lateral and dorsal funiculi. Apoptotic cells, detected by TUNEL staining, appeared in lateral funiculi of spinal cord injured rats. The application of SB203580 decreased the number of apoptotic cells. The SB203580-treated animals showed no significant degeneration of myelin structure. These results suggest that inhibition of p38-MAPK is one candidate for therapeutic agents against neurological deficits after spinal cord injury.

Microglial proliferation and activation have been reported to occur after several central nervous system injuries. In this study, we tested the effects of adenosine triphosphate (ATP) on cultured microglia obtained from the spinal cord of rat embryos. The amounts of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta and interleukin 6 released from the microglia, which were stimulated by lipopolysaccharide (LPS; 100 ng/ml), were inhibited by the simultaneous addition of ATP in a dose dependent manner (10-300 microM). We examined the effect of several endogenous purines (ATP, ADP, CTP, UDP, UTP) and P(2)y receptor agonists (ADPbetaS and 2-methylthio-ATP) on LPS-induced TNF-alpha release. The rank order of inhibitory potency of endogenous purines on TNF-alpha release was: ATPADPUTPUDPCTP. The latter three were much less potent than the former two. The addition of 10 microM 2-methylthio-ATP showed a potency similar to 100 microM ATP. The addition of ADPbetaS, however, showed less effect. These endogenous purines and selective ATP receptor agonists showed a similar inhibitory effect in their rank order on LPS-induced interleukin 6 release. We demonstrate that ATP inhibits cytokine release from LPS-activated microglia via metabotropic receptors. The application of P(2)y receptor agonists might be considered as a pharmacological treatment of several pathological conditions of the spinal cord, including toxic immunoreactions.

In order to investigate the mechanism of delayed progressive or secondary neuronal damage after the spinal cord injury, we developed a mild-compression injury model in the rat thoracic spinal cord. Our compression device consists of a soft silicone point of contact to the dura, in order to prevent violent injury that may cause axonal tears or hemorrhages in the spinal cord. Since rats often assume a 'standing' posture, i.e. raising head with lifting their fore-limbs, damage to the thoracic spinal cord was evaluated by measuring the frequency of 'standing', which effectively indicates hind limb function. Twenty-four hours after compression by a 20 g weight for 10 or 20 min, the standing frequency of the injured rat was almost the same as that of sham animals that underwent laminectomy without compression. However, the standing frequency decreased with time; the frequency of standing at 72 h was approximately 30-50% that of sham animals. In the compressed spinal cord tissue, microglial cells, detected by lectin staining, proliferated with time. An enormous amount of microglia was observed at 48 and 72 h after compression, although only a small amount of cells were positive to lectin staining at 24 h after the compression. These results suggest that our mild-compression spinal cord injury model showed late-onset or delayed neuronal damage that may be related to pathological microglia proliferation.

Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves’ Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.

Release of nitric oxide and TNF-alpha, a toxic cytokine, have been reported to accelerate neuronal damage under several pathological conditions, such as trauma or ischemia in the central nervous system. In the present study, we tested the effect of alprostadil alfadex, a prostaglandin E1 analog, on cultured microglia from the rat spinal cord. The cultured microglia were exposed to lipopolysaccharide (LPS) (100 ng/ml), an endotoxin, for 24 h, then the released nitric oxide and TNF-alpha in the culture media was analyzed. The released nitric oxide was detected by the Griess reaction and released TNF-alpha was measured using ELISA method. The LPS-induced nitric oxide release was inhibited by the simultaneous addition of alprostadil alfadex in a dose-dependent manner (0.1-100 microM). The LPS-induced TNF-alpha release was also inhibited by alprostadil alfadex addition (0.1-100 microM). The IC50 values of alprostadil alfadex on nitric oxide and TNF-alpha release were about 1 and 10 microM, respectively. These results suggest that prostaglandin E1 possibly protects spinal cord neurons from several types of neurodegenerative damage, not only via increased blood supply, but also via inhibition of pathological immunoreactions of activated microglia.

Microglia, immune cells in the central nervous system, have been reported to proliferate and become activated in damaged neuronal tissue. After experimental spinal cord injuries, proliferation of microglia in the injured site has been detected. Activated microglia release many substances which modulate secondary neuronal degeneration and regeneration after spinal cord injury. However, whether microglia are good or bad is under debate. In the acute phase of spinal cord injury, several papers suggested detrimental effects of activated microglia. Released glutamate and oxygen free radicals and cytokines, including TNF-α and interleukins, may directly induce damage of neurons and oligodendrocytes. On the other hand, activated microglia shows a neuroprotective effect via the production of neurotrophic factors.

Background: We report 8 years of follow-up after decompression to treat cervical myelopathy in a patient with Coffin–Lowry syndrome (CLS). CLS is a rare X-linked semidominant syndrome associated with growth and psychomotor retardation, general hypotonia, and skeletal abnormalities. In this patient, the spinal cord was compressed by calcium pyrophosphate crystal deposition in the cervical yellow ligament (YL). To date, only 1 report has described clinical features after surgery for calcified cervical YL in CLS. Methods: A 15-year-old male with tetraplegia secondary to compression of the cervical spinal cord induced by a hypoplastic posterior arch of C1 and calcification of the YL from C2 to C7 was treated surgically with laminectomy from C1 to C7. The patient's history, clinical examination, imaging findings, and treatment are reported. The patient was incapable of speech because of mental retardation, so he could not describe his symptoms. Gait disturbance worsened over the 2 months before admission to our hospital. At admission, the patient could not move his extremities, and tendon reflexes of the upper and lower extremities were significantly increased. Computed tomography of the cervical spine showed YL calcification from C2 to C7. Magnetic resonance imaging showed consecutive compression of the cervical spinal cord. We diagnosed quadriplegia secondary to cervical cord damage and performed emergency surgery. Results: During C1–C7 laminectomy, YL calcification in C2–C7 was observed. The calcification was confirmed as calcium pyrophosphate by crystal analysis. Quadriplegia gradually resolved, and almost disappeared by 2 weeks after the operation. Cervical hyperlordosis was observed in radiographs starting from 1 month after the operation, but it has not progressed and is not associated with any symptoms. Conclusions: The efficacy of decompression continued, and no postoperative complications have occurred during at least 8 years of follow-up.

Introduction Congenital hypoplasia of the atlas has rarely been reported. Myelopathy caused by the complete absence of the posterior arch of the atlas has not been reported. This case report describes the diagnosis and successful treatment of a myelopathy due to the complete absence of the posterior arch of the atlas. Case presentation A 59-year-old Japanese man experienced pain in his nuchal region with progressive spasticity, numbness and hypesthesia in his upper and lower limbs. Deep tendon reflexes in his upper and lower limbs were increased. The complete absence of the posterior arch of the atlas and atlantoaxial instability were found in a roentgenogram. Magnetic resonance imaging detected high signal intensity on T2-weighted images in his spinal cord at the level of cervical vertebrae 1 to 2. Our patient underwent posterior occipito-C4 fixation with pedicle screws. After the operation, the pain in his nuchal region disappeared and his symptoms of myelopathy improved. Only slight numbness of his upper limbs remained. Conclusions This is the first report of myelopathy due to the complete absence of the posterior arch of the atlas.

Chondroitin sulfate proteoglycans are formed in scar tissue after a spinal cord injury and inhibit axon regrowth. The production of neurocan, one of these chondroitin sulfate proteoglycans, in cultured spinal cord astrocytes increased after the addition of epidermal growth factor (EGF) in a dose-dependent manner (2-200 ng/ml). In astrocytes stimulated by 20 ng/ml of EGF, neurocan production was inhibited after the addition of the p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580: 3-10 μM) in a dose-dependent manner. These results suggest that the activation of p38 MAPK is one of the mechanisms of neurocan production in EGF-stimulated astrocytes. The p38 MAPK inhibitor may reduce neurocan production and accelerate axonal regrowth after a spinal cord injury.

A case report and review of previous literature.To describe the diagnosis and successful treatment of an intraspinal retro-odontoid cyst associated with an os odontoideum.Retro-odontoid cysts associated with atlantoaxial instability are extremely rare. Direct excision of the cysts has commonly been performed for the surgical treatment of myelopathy.A retro-odontoid cyst in a 58-year-old woman with os odontoideum was treated surgically by posterior fixation between C1 and C3 without resection of the retro-odontoid mass. The patient's history, clinical examination, imaging findings, and treatment are reported.The patient experienced walking difficulty, numbness in the upper and lower limbs, and hypesthesia in both hands. Congenital C2/3 fusion and atlantoaxial instability associated with an os odontoideum were found in the radiographs. Magnetic resonance imaging detected a round retro-odontoid mass, which compressed the spinal cord. The mass showed uniform low intensity on T1-weighted images and uniform high signal intensity on T2-weighted images. Gadolinium-diethylenetriaminepenta-acetic acid-enhanced T1-weighted images showed rim enhancement of the mass with no internal enhancement. Three months after the operation, the mass was no longer visible in a magnetic resonance imaging examination and the patient completely recovered motor function in her extremities.Posterior fixation without resection was successfully used to eliminate a retro-odontoid cyst associated with atlantoaxial instability.

✓ Periosteal chondromas located in the spine are rare. The authors document a case of periosteal chondroma in the lumbar spinal canal of a 77-year-old man. The patient had severe pain in his right leg and used a wheelchair because of weakness in both legs. Magnetic resonance imaging revealed a round tumor that was hypo- or isointense on T1-weighted images and uniformly hyperintense on T2-weighted images. Administration of gadolinium-diethylenetriamine pentaacetic acid resulted in margin enhancement on T1-weighted images. During the operation, a round tumor 1.5 cm in diameter was found on the surface of the anterior wall of the L-3 lamina. Histological examination revealed that the tumor consisted of chondroid tissue with typical chondrocytes, indicating that it was a periosteal chondroma.

A pathological glia activation, stimulated by inflammatory proteins, beta-amyloid, or brain ischemia, is discussed as a common pathogenic factor for progressive nerve cell damage in vascular and Alzheimer dementia. A critical point seems to be reached, if the cytokine-controlled microglial upregulation causes a secondary activation of astrocytes which loose the negative feedback control, are forced to give up their physiological buffering function, and may add to neuronal damage by the release of nitric oxide (NO) and by promoting toxic beta-amyloid formation. A strengthening of the cyclic adenosine-5',3'-monophosphate (cAMP) signaling exerted a differential inhibition of the stimulatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) released from cultured rat microglia, but maintained the negative feedback signal IL-6; cAMP inhibited also the release of free oxygen radicals (OR) but not of NO. Reinforcement of the NO-induced cyclic guanosine monophosphate (cGMP) increase by blockade of the phosphodiesterase (PDE) subtype-5 with propentofylline counterbalanced the toxic NO action that causes with OR neuronal damage by peroxynitrate formation. In rat cultured astrocytes, a prolonged cAMP elevation favored cell differentiation, the expression of a mature ion channel patter, and an improvement of the extracellular glutamate uptake. Cyclic AMP signaling could be strengthened by PDE blockade and by raising extracellular adenosine, which stimulates A2 receptor-mediated cAMP synthesis. Via an A1 receptor-mediated effect, elevated adenosine was found to overcome a deficient intracellular calcium mobilization resulting from an impaired muscarinic signaling at pathologically decreased acetylcholine concentrations. We suggest that pharmaca, which elevate extracellular adenosine and/or block the degradation of cyclic nucleotides, may be used to counteract glia-related neuronal damage in dementing processes.

The effects of mild hypothermic treatment on motor functions and immunological changes were tested in rats after spinal cord injuries. To simulate spinal cord injury, the rat spinal cord was exposed at the 11th vertebra and compressed using 20 g of weight for 20 min. The temperature of the animals was fixed for 1 h from the beginning of the compression period at 33°C and 37°C for the mild hypothermic treatment and the control, respectively. At 24 h after injury, the frequency of vertical movement (standing) during a 1-h period, which reflected rat hind-limb function, of both the control animals and the hypothermia-treated animals was about 45% that of the sham animals, which had undergone laminectomy without compression. The hind-limb function of hypothermia-treated animals gradually increased and completely recovered at 72 h after injury, whereas the control animals showed little recovery. A marked proliferation of positive isolectin-staining microglia was observed in the control animals from 48 h after the injury. On the other hand, in both hypothermia-treated and sham animals, a small number of microglia were observed up to 72 h after the injury. These results suggest that mild hypothermia is an effective treatment for secondary neuronal damage after spinal cord injury, and inhibition of microglial proliferation may be one of the mechanisms of the mild hypothermic effect.